LINE-1 retrotransposition in neurons

LINE-1 retrotransposons are sections of DNA which are capable of copying themselves into another part of the genome. Although traditionally considered to merely epitomize the concept of the selfish gene, more recently they have been suggested to have physiological functions. Here I discuss the incredibly fascinating hypothesis that LINE-1 retrotransposons may be important in generating neuronal variation.

Selfish genes and retrotransposons

Personally, I think that there's something problematic about Dawkins' reductionism in his book The Selfish Gene. In that book, Dawkins explains that the gene can be considered as the smallest unit of selection, in which case the "purpose" of every single gene is to independently copy itself as far as it can. We are vehicles for our genes, who share a common interest - the organism - in order to propagate themselves.

Don't get me wrong, I agree that it's practically a truism to say that genes that can contribute to their own survival will as a result be better at replicating. My problem is with the conceptualisation of genes as monads. Dawkins seems to believe that the survival of the organism can be calculated as the sum of its genes.

The most important lesson of developmental biology has been that there is no function without context. I can't elaborate too much at this point, but suffice to say that in the same way that it would be impossible to read an alien language without some sort of reference, and in the same way that a protein could not be assigned a function without a cellular context, so too a gene has no survival-index without the context of its host organism, (and taking a step further back, without the context of its host organism's environment).

It is now interesting to consider unique cases like transposons. Transposons are segments of DNA which are capable of "jumping" around the host organism's genome. A category of transposon are the retrotransposons, which are segments of DNA which jump around the genome by copying themselves and then inserting the copy into another part of the genome. Transposons, including retrotransposons are often considered to be classical selfish genes. They don't seem to contribute to the organisms well-being at all, and their entire purpose is to replicate as much as possible irrespective of the organism.

As you can probably guess, the picture is far more interesting that all that. But first I need to say a few words about different aspects and mechanisms of variation in neurons.

Neuronal variation

It's common when trying to communicate the incredibility of the human brain to quote the number of neurons, or the number of connections, and then to try and quantitatively compare that with an electronic computer. That's all well and good, but it's not enough. Discussing the brain as a network of nodes connected in parallel ignores the complexity of that system. It ignores the manner in which individual neurons process information inputs, how that processing affects future processing, and the type of signals involved. It also ignores the fact that neurons are not a homogeneous population. There are various convenient ways to differentiate neurons, for instance their morphology, what receptors they present, what neurotransmitters they use to signal, and so forth.

An extraordinary diversity is found within the neuronal population. There might be as many as 10,000 types of neuron, although the definition of neuronal type is debated. Diversity exists between individual cells within a neuronal subtype, highlighting the importance of single neurons in the network. Even neurons with a similar morphology can differ in important molecular details, expressing different combinations of ion channels, for instance, providing cells with various excitation thresholds and distinctive firing patterns. However, how and when neuronal diversity is generated remains unknown.(Muotri & Gage 2006)

This complexity is presumably required by the brain in order to manifest its higher-order capacities, including perhaps self-awareness. Different mechanisms are responsible for generating the neuronal variation, including alternative transcription start sites and RNA splicing. Retrotransposition may also contribute to neuronal variation.

L1 and somatic mosaicism

The next paragraph, and the next paragraph alone, depends on evidence heard second hand; my "source" heard Fred Gage give a talk. Gage is a leader in this particular sub-field, and is the primary investigator on almost all of the papers referenced for this writeup.

The story begins with Fred Gage and colleagues studying neuronal precursor cells. These are cells that aren't quite neurons yet, but can mature into the various forms of neurons. As part of their experiments the group sequenced their cells, but something strange kept occurring: the more times these precursor cells divided the bigger their genomes got! After ruling out some sort of contamination, they took at look at what the cells were transcripting, and realised that these cells had a lot of retrotransposon activity. In particular, the retrotransposon called Long interspersed repetitive element-1, which abbreviates to LINE-1 which abbreviates to L1.

The very first paper showing that L1 could contribute to neuronal heterogeneity was published in 2005 in the prestigious science journal Nature. The paper demonstrated that when precursor cells begin to transform into neurons, they reduce the amount of Sox2 (transcription factor). Sox2 normally binds to the DNA near L1 elements to prevent them from copying themselves, so when there is less Sox2 then there is increased L1 retrotransposition. This seems to be a phenomenon restricted somewhat to neuron development, and might involve those precursor cells remodeling their chromatin (DNA) to alter L1 availability. Finally, the paper demonstrated the L1 is active during neuron development in actual animals.

Big deal? Yes. First of all, the facts until now had said that transposon activity is only present in germ line cells (ie. those that produce sperm and ovum), but is soon turnedoff. This paper shows that normal cells have the potential for transposon activity, and more-so, that neurons preferentially allow it! It also implies that even inside the same brain, different areas are not completely genetically identical. Different neurons may have experienced different transposon activities, in which L1 was copied a different number of times and to different locations in the genome. And as a consequence, where those L1 insertions affect genes, the actual neurons' gene activity may differ.

These results were followed up with publications reporting that L1 is similarly active in humans, and can even be found in adult brains, although it's not yet clear whether how this relates to adult neurogenesis(Coufal 2009); a third paper elaborated on the molecular mechanisms involved in L1 activation (Moutri 2010).

If valid, the implications of physiological retrotransposition in neurons could be huge. I stress "physiological" because that would imply that this feature of neuronal development has been selected for. If that were the case it would highlight the fact that although transposons considered in and of themselves display a parasitic function,without regard for their host, this is not the whole story. L1 as a DNA parasite, and L1 as a mechanism for variation are both "selfish". They both result in increasing the capacity of L1 to propagate. The difference is whether we call L1 selfish in its capacity as a gene, or as an organism. Because I hold that genes have no meaning, no natural function, without their host context, I'd suggest that only the second possibility is meaningful.

Even in a perfectly controlled experiment some animal traits, like fear and learning, appear to display an unavoidable variation. This variation results in the well known bell curve response, and has been termed intangible variance. This intangible variance might be partially explained by appealing to L1: "L1-mediated retrotransposition could be a mechanism that alters neuronal function in individuals, thereby broadening the spectrum of behavioral phenotypes that can originate from any single genome" (Singer 2010).

One of the most incredible thing about people is how much they vary. (The other incredible thing is obviously their similarity). It seems so obvious and commonsensical that people should be tweaked slightly differently in myriad ways that we don't question it. Even when identical twins have differences we're only mildly distracted, after all, each person is their own person. But maybe not. Maybe it is this inherent fallible randomness that makes us possible - that transforms us from an anonymous ego into a particular you and me.

Some other things that spring to mind as possibly being applicable to L1-mediated neuronal variance: adult neurogenesis, anti-depressants, and neuronal pruning during early development.